Congenital hypophosphatasia is associated with poor prognostic expectations, as over 50% of newborns affected by the condition eventually succumb to respiratory defects accompanied by neurological complications, dehydration and fever.

The majority of newborn patients initially display no pathologic symptomatology compatible with hypophosphatasia until the age of 6 months. A given delayed growth, limited appetite and hypotonic characteristics have been reported, but the symptoms remain non-specific during the first months of life. After the age of 6 months, bone abnormalities begin to manifest, including partially or non-ossified bones, irregular vertebral bodies resembling a butterfly in shape and smaller bone size. The ulna or fibula may exhibit the so-called Bowdler spurs, which are essentially osteochondral projections. Pediatric patients experience pain originating from the bones, baby teeth are shed earlier than normal and calcium deposits can be found on the kidneys. Severe complications also include epileptic encephalopathy responsive to vitamin B6 administration [2] and early closure of skull joints which leads to elevated intracranial pressure.

In the case of later-onset hypophosphatasia, patients have usually been completely asymptomatic during the previous years, even though some may report frequent foot or joint pain [3] dating back to their childhood years. The condition is commonly diagnosed incidentally, upon the revelation of diminished alkaline phosphatase levels in a blood test. Many patients may have lost their teeth too early in their childhood. Hypophosphatasia causes the bones to be vulnerable to fractures and stress fractures, due to a defective composition. If an individual suffers from odontohypophosphatasia, the only symptom is an abnormally early loss of adult teeth.

Irrespective of the age of diagnosis, patients with hypophosphatasia may exhibit persisting bone edema (adults), hyperprostaglandinism (children) and osteomyelitis [4]. These findings indicate a close connection of the condition with metabolic disorders.

The first step towards evaluating a case of potential hypophosphatasia is laboratory testing, including levels of the following:

Blood tests

• Alkaline phosphatase: low levels are consistent with the condition that the patient does not need to have fasted prior to the examination.
• Phosphate analysis: the patient needs to have fasted.
• Phosphorus
• Magnesium
• Calcium
• Parathyroid hormone
• Vitamin D
• Creatinine
• PLP: elevated. Its levels may be affected by vitamin B6 supplementation.
• PPi

Urine tests

• PEA: elevated levels are consistent with the condition but are not pathognomonic.

The next diagnostic step involves radiologic examining of the skeleton. Adults usually exhibit multiple pseudofractures and partially healed stress fractures. Pediatric patients exhibit incomplete mineralization, rachitic abnormalities and spurs in the elbows and knees. Early synostosis of the skull can also be observed. The radiologic findings depend on the severity of each case.

Ultrasonography can be used to detect kidney calcinosis. Patients who are affected by odontohypophosphatasia solely display diminished maxillary density.

A biopsy sample ban be obtained from a bone, but this procedure is mainly carried out for research purposes. A histological analysis is expected to reveal increased osteoid indices, such as thickness and osteoid surface per bone surface, inadequate mineralizing surface and a decreased bone formation rate. Regional cartilage calcification can also be observed. Osteoblasts and osteoclasts are functional but membrane ALP activity is absent, as illustrated by a histochemical analysis.

No cure is available for hypophosphatasia and the rarity of the condition affects the prospects of thorough clinical studies in a negative way. Possible conservative treatment plans include the administration of non-steroidal anti-inflammatory drugs which seemed to relieve pediatric patients from pain [5] [6] and reduce the subsequent metabolic inflammation [4]. Phosphate intake should be also reduced. Teriparatide further seemed to improve the healing of recurrent stress fractures [7].

An experimental treatment was attempted in 1997: a patient aged 8 months old received a bone marrow transplant as treatment for hypophosphatasia and displayed considerable clinical improvement [8]. Another treatment that was carried out in another pediatric patient involved the use of bone fragments and osteoblasts derived from a culture [9]; the patient grew up to exhibit a milder clinical picture than expected. Lastly, researchers inactivated the plasma cell membrane glycoprotein-1 (PC-1) gene in laboratory mice [10], something which actually restored the characteristics of affected rodents. Both genetic therapy and enzyme supplementation therapy are currently being under research, with the aim of developing an adequate hypophosphatasia treatment.

The congenital type of hypophosphatasia is a fatal condition and only half of the pediatric patients who develop the disease during infancy eventually survive. Individuals affected by the later-onset, adult type, as well as those exhibiting odontohypophosphatasia exhibit the same mortality rate as the rest of the population.

Hypophosphatasia has been genetically mapped; the ALPL gene responsible for all the disease types, both early and adult, is found at the 1p36.1-34 band. ALPL encodes for tissue nonspecific alkaline phosphatase. Hundreds of variants have been detected over the years and regardless of the type of hypophosphatasia, it can be passed down to offspring via both an autosomal dominant and a recessive pattern.

The most severe type of hypophosphatasia is particularly observed amongst some specific populations, like the Canadian Mennonites with a frequency of around 1 in 2,500 births. Generally, the condition is believed to affect approximately 1 in 100,000 newborns in the USA [1]. Data regarding its incidence on a worldwide scale are not available.

Occurrences of hypophosphatasia that arise within 6 months after birth are extremely severe, with half of the newborns succumbing to complications affecting the respiratory tract. In the cases of later onset usually patients reach the age of 18; however, frequent and troubling complications arise. Rachitic deformities are common amongst hypophosphatasia patients, as are frequent fractures, delayed or incomplete healing, calcium deposits on the kidneys, seizures and elevated intracranial pressure. Skeletal weakness and softness renders an individual unstable, as the bones fail to support their weight and are fractured. Therefore, approximately 1/4 of the patients move with the aid of a wheelchair or other walking device.

In general, hypophosphatasia exhibits no racial predilection and affects both genders and age groups.

The human organism functions with the aid of distinct isoforms of alkaline phosphatase, one of which is TNSALP. TNSALP stands for tissue nonspecific alkaline phosphatase and although its function has yet to be fully understood by the medical community, it is believed to mediate matrix mineralization and hydrolyze pyridoxal phosphate (PLP), phenethylamine (PEA) and diphosphate (PPi). The genetic location of the TNSALP gene is known to be 1p36.1.

Individuals suffering from hypophosphatasia display low levels of TNSALP; as a result, the levels of PPi increase, and this impairs the formation of hydroxyapatite crystals and disrupts the equilibrium between phosphate and calcium.

As a genetic condition, hypophosphatasia cannot be prevented.

Hypophosphatasia is a condition which causes inadequate deposition of minerals on bone tissue and teeth during their formation.

There are various degrees of severity; the types associated with the severer symptomatology are early onset (arising during the first years of life) or congenital. Similar to rickets, hypophosphatasia does not allow for a normal composition of bones and teeth, leading to soft, weak bones that are susceptible to fractures and teeth that tend to fall prematurely. Children who are born with hypophosphatasia exhibit shortened extremities, soft bones on the skull, abnormally bent knees and chest structural abnormalities; later on in life they show poor feeding habits and hypercalcemia, which greatly impairs renal function in addition to frequent vomiting. In many cases, the first symptom indicating the presence of hypophosphatemia in children is the premature loss of baby teeth.

Late onset hypophosphatemia regards cases which appear during the adult life and are typically not as severe as early onset disease types. Osteomalacia is the prevalent symptom, which means "soft bones" and is a term derived from the Greek "osto= bone + malakos= soft". Adults are very susceptible to bone fractures and early teeth loss, as well as persistent pain due to the frequent fractures.

Lastly, there is a sub-type of Hypophosphatasia which solely impairs teeth formation, called "odontohypophosphatasia". Adult individuals suffer only dental problems and early teeth loss but no other bone abnormalities.

Hypophosphatasia is a rare hereditary bone disease that is caused by abnormally low levels of alkaline phosphatase (ALP). ALP is an enzyme which greatly contributes to the formation of a strong skeleton and correctly developed bones and teeth. Individuals who suffer from hypophosphatasia have weak bones which lack in density and subsequently defective teeth. The disease exhibits various degrees of severity and there are individuals who merely have low levels of ALP in their blood, without any other symptoms.

A person can be born with hypophosphatasia or be diagnosed with it during their infancy, childhood, or adult life. Individuals who are affected by odontohypophosphatasia only experience teeth problems and no skeletal deformities.

Patients with this condition suffer frequent fractures and stress fractures. Their skeleton is not properly developed and various abnormalities can occur, either visible or not. Teeth are usually lost quite early in childhood. When the chest structure is too damaged, pneumonia is bound to occur in a more frequent manner as in healthy individuals.

As for treatment options, there is no treatment for hypophosphatasia. Patients have in the past been treated with various medications which were conservative and not able to cure the disease. Bone marrow transplant and bone donors have been used, but no definitive treatment plan has been developed yet.

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